Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade

Abstract

Immune checkpoint blockade (ICB) has transformed the treatment landscape of multiple malignancies, producing durable responses and long-term survival in subsets of patients with advanced cancer. However, the clinical benefit of ICB remains largely restricted to tumors displaying pre-existing immune activation, high tumor mutational burden (TMB), or deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) status. In contrast, the vast majority of solid tumors retain proficient mismatch repair (pMMR) function, exhibit limited neoantigen diversity, and frequently display an immunologically “cold” tumor microenvironment, resulting in primary resistance to checkpoint inhibition. Here, we propose the concept of induced mismatch repair deficiency (idMMR), a therapeutic strategy aimed at transiently and reversibly suppressing the core mismatch repair proteins MLH1 and MSH2 in pMMR tumors. We hypothesize that temporary impairment of mismatch repair activity may create a controlled hypermutagenic window during which replication-associated insertion and deletion events accumulate within coding microsatellite regions, with the potential to generate frameshift-derived neoantigens that may enhance tumor immunogenicity. Subsequent restoration of endogenous mismatch repair function would restore basal mutagenesis while preserving newly generated antigenic targets for immune recognition. Unlike constitutive mismatch repair deficiency, idMMR would be pharmacologically controlled and potentially reversible through RNA-based therapeutic approaches. We discuss the biological rationale supporting this hypothesis, the potential immunological consequences of transient mismatch repair suppression, major safety considerations, mechanisms of resistance, and key experimental studies required for validation. Although several critical assumptions remain untested, idMMR may represent a novel framework for converting immunologically cold tumors into ICB-responsive tumors.